Cerebral ischemia in the perioperative period is a major risk factor for stroke, encephalopathy, and cognitive decline after cardiothoracic surgery. After coronary artery bypass grafting, both stroke and encephalopathy can result in poor patient outcomes and increased mortality. Neuroprotection aims to lessen the severity and occurrence of further injury mediated by stroke and encephalopathy and to aid the recovery of conditions already present. Several pharmacological and non-pharmacological methods of neuroprotection have been investigated in experimental studies and in animal models, and, although some have shown effectiveness in protection of the central nervous system, for most, clinical research is lacking or did not show the expected results. This review summarizes the value and need for neuroprotection in the context of cardiothoracic surgery and examines the use and effectiveness of several agents and methods with an emphasis on clinical trials and clinically relevant neuroprotectants.